Germline pathogenic variants in 7,636 Japanese patients with prostate cancer and 12,366 controls
Menée au Japon à partir de l'ADN des cellules germinales de 12 366 témoins et de 7 636 patients atteints d'un cancer héréditaire de la prostate, cette étude identifie, à l'aide du séquençage de 8 gènes de prédisposition (ATM, BRCA1, BRCA2, BRIP1, CHEK2, HOXB13, NBN et PALB2), 136 variants pathogènes, puis analyse la contribution de chacun d'eux dans le développement de la maladie
Background : Genetic testing has been conducted in patients with prostate cancer (PCa) using multi-gene panels, but no centralized guidelines for genetic testing exist. To overcome this limitation, we investigated the demographic and clinical characteristics of patients with pathogenic variants. Methods : We sequenced eight genes associated with hereditary PCa in 7,636 unselected Japanese patients with PCa and 12,366 male, cancer-free controls. We assigned clinical significance for all 1,456 variants using the American College of Medical Genetics and Genomics guidelines and ClinVar. We compared the frequency of carriers bearing pathogenic variants between cases and controls to calculated PCa risk in each gene and documented the demographic and clinical characteristics of patients bearing pathogenic variants. All statistical tests were two-sided. Results : We identified 136 pathogenic variants, and 2.9% of patients and 0.8% of controls had a pathogenic variant. Association with PCa risk was statistically significant for variants in BRCA2 (P < 0.001, OR = 5.65, 95% CI = 3.55-9.32), HOXB13 (P < 0.001, OR = 4.73, 95% CI = 2.84-8.19), and ATM (P < 0.001, OR = 2.86, 95% CI = 1.63-5.15). We detected recurrent new pathogenic variants such as p.Gly132Glu of HOXB13. Patients with pathogenic variants were 2.0 years younger at diagnosis, more often had smoking and alcohol drinking histories, and family histories of breast, pancreatic, lung, and liver cancers. Conclusion : This largest sequencing study of PCa heredity provides additional evidence to the latest consensus among clinicians for developing genetic testing guidelines for PCa.